Fluorinated Cyanine For Fluorine-19 Magnetic Resonance/Fluorescence Bimodal Imaging Of Lung Cancer

Lung cancer is a prevalent form of cancer,and the use of ¹⁹F magnetic resonance imaging（MRI）shows promise in its diagnosis.Unlike other imaging techniques,¹⁹F MRI offers several advantages,including the absence of ionizing radiation,no limitations in depth of penetration,and no interference from background signals in vivo.On the other hand,fluorescence imaging provides high sensitivity and ease of use,allowing for the visualization and analysis of microscopic physiological events,such as cells and sub-cells.The combination of ¹⁹F MRI and fluorescence imaging,known as dual-modality imaging,holds great potential in providing comprehensive biochemical information about lung cancer.This approach enables visualization at both the anatomical and molecular levels,offering a visual tool for rapid and accurate diagnosis as well as research in this field.However,the development of bimodal ¹⁹F MRI/fluorescence probes for lung cancer imaging is challenging due to the independent signal sources of most probes and the poor spatial and temporal matching of their response changes.This mismatch poses a hurdle in achieving high-contrast imaging for lung cancer using bimodal probes.The primary objective of this dissertation is to develop molecular probes that combine¹⁹F magnetic resonance and fluorescence signals for enhanced imaging of lung tumors.The aim is to optimize the probe design to integrate both signals effectively,improving specificity and sensitivity.Ultimately,this research achieves ¹⁹F magnetic resonance/fluorescence bimodal imaging of lung tumors.Within this dissertation,three imaging probes suitable for murine lung cancer models were designed and synthesized.These probes incorporate fluorine-containing groups and tumor microenvironment response groups into cyanine backbones.The main contents of this dissertation are as follows:（1）A bimodal probe integrating ¹⁹F magnetic resonance and fluorescence signals was synthesized by modifying cyanine as the template molecule.This probe demonstrates prolonged residence in the lung and effective accumulation at tumor sites without the need for a targeting group.It has significant applications in monitoring and assessing murine lung cancer models in situ.（2）The specificity of the probe plays a crucial role in reliable lung cancer diagnosis.To enhance the probe’s specificity for lung cancer imaging,a nitro group was introduced into the fluorinated cyanine molecule as a recognition domain for nitroreductase,which is highly elevated in hypoxic tumors.The enzyme-catalyzed conversion of nitro to amine groups triggers simultaneous changes in emission wavelengths and chemical shifts.The fluorescence signal can detect nitroreductase at concentrations up to 1.5μg/m L,while the magnetic resonance signal shows a proportional relationship with nitroreductase concentrations ranging from 10 to 50μg/m L.This probe enables ¹⁹F magnetic resonance/fluorescence bimodal imaging for specific identification of hypoxic tumor regions in murine lung cancer models.（3）The response sensitivity of the probe directly impacts the imaging quality,and improving this sensitivity while maintaining imaging specificity is of great significance.A fluorinated cyanine polymer,PEG-SS-FCy7,was designed and synthesized.It self-assembles into polymer micelles with reduced glutathione in an aqueous solution system.The release of cyanine from the polymer,triggered by changes between"on"and"off"states,enhances the responsiveness of both fluorescence and magnetic resonance signals.In vitro fluorescence imaging and ¹⁹F MRI can quantify reduced glutathione concentrations ranging from 10 to 150μM and 1 to 10 m M,respectively,with maximum signal enhancements of17 and 63 times,respectively.This reduced glutathione-activated ¹⁹F magnetic resonance/fluorescence bimodal imaging accurately identifies lung cancer in murine models.In conclusion,this dissertation developed three ¹⁹F magnetic resonance/fluorescence bimodal imaging probes by fluorinating cyanine,targeting nitroreductase,and reducing glutathione in the tumor microenvironment.These probes enhance specificity and contrast,enabling precise imaging of murine lung cancer models in situ.